Objectives This study sought to investigate the benefit of papillary muscle surgery on long-term clinical outcomes of patients with ischemic MR.

Methods Ninety-six patients with severe ischemic MR were randomized to either undersizing restrictive mitral annuloplasty (RA) or papillary muscle approximation with undersizing restrictive mitral annuloplasty (PMA) associated with complete surgical myocardial revascularization. The primary endpoint was change in left ventricular end-diastolic diameter (LVEDD) after 5 years, measured as the absolute difference from baseline, which was evaluated by paired Student t tests. Secondary endpoints included changes in echocardiographic parameters, overall mortality, the composite cardiac endpoint (major adverse cardiac and cerebrovascular events [MACCE]), and quality of life (QOL) during the 5-year follow-up.

Results At 5 years, mean LVEDD was 56.5 ± 5.7 mm with PMA versus 60.6 ± 4.6 mm with RA (mean change from baseline −5.8 ± 4.1 mm and −0.2 ± 2.3 mm, respectively; p < 0.001). Ejection fraction was 44.1 ± 6% in the PMA group versus 39.9 ± 3.9% in the RA group (mean change from baseline 8.8 ± 5.9% and 2.5 ± 4.3%, respectively; p < 0.001). There was no statistically significant difference in mortality at 5 years, but freedom from MACCE favored PMA in the last year of follow-up. PMA significantly reduced tenting height, tenting area, and interpapillary distance soon after surgery and for the long-term, and significantly lowered moderate-to-severe MR recurrence. No differences were found in QOL measures.

Conclusions Compared with RA only, PMA exerted a long-term beneficial effect on left ventricular remodeling and more effectively restored the mitral valve geometric configuration in ischemic MR, which improved long-term cardiac outcomes, but did not produce differences in overall mortality and QOL.

The reported incidence of ischemic mitral regurgitation (MR) among persons who experience myocardial infarction is up to 39% (1,2). Ischemic MR is a consequence of a geometric disturbance of the mitral valve configuration due to papillary muscle injury and displacement (3–7). Functional valve incompetence centers on the abnormal imbalance between closing and tethering forces with otherwise normal leaflets (8). Annular dilation, enlargement of the left ventricular (LV) chamber, and abnormal papillary muscle displacement with apical and lateral migration are consequences of the tethering forces. Reduction of LV contractility, global LV dyssynchrony, papillary muscle dyssynchrony, and altered mitral systolic annular contraction are expressions of the decreased closing forces (8) that lead to impaired leaflet coaptation and a variable degree of MR, which (often concurrently with the residual ischemia), in turn, can affect the state of ventricular filling, heart rhythm, and afterload (9,10). The 2014 American College of Cardiology Guidelines for patients with severe ischemic MR advocated consideration of mitral reparative surgery as an adjunct to treatment of the primary underlying pathology with coronary revascularization (3). However, published reports are not conclusive as to which of the currently proposed valve repair approaches is superior, and specifically, if standard annuloplasty requires an auxiliary subvalvular intervention to attenuate the incidence of MR recurrence (11). The latter point takes into account the accumulating evidence that suggests that preservation and restoration of papillary muscle function by relocation or approximation are associated with longer overall survival (12–14).

A recent relevant randomized study claimed that a mitral replacement strategy was superior to repair in severe ischemic MR, in terms of recurrence of moderate-to-severe MR at 1 (1) and 2 years of follow-up (15). However, although this trial showed no significant between-group differences in LV reverse remodeling, MV repair with annuloplasty produced a significantly higher frequency of heart failure–related events; despite the increased recurrence of MR, no significant differences were found in major cardiac adverse event rates, overall mortality, or quality of life (QOL) (1,15). The results of this study constitute a significant landmark in decision making in ischemic MR, addressing the delicate tradeoff between mitral replacement, which provides a more durable correction of the MR at the cost of increased periprocedural mortality, and mitral repair, which guarantees a reduced perioperative risk burden but provides less satisfactory long-term results (16,17). However, as the investigators also pointed out, careful consideration of the mechanisms that underlie recurrence of MR after annuloplasty might elucidate explanations for the unsatisfactory outcomes. Factors, such as augmented leaflet tethering caused by the anterior displacement of the posterior leaflet (18), the role of adjunctive subvalvular procedures that may potentially influence recurrence of MR after annuloplasty (19), as well as the progressive adverse global and localized LV remodeling related to incomplete revascularization (20) were not addressed. Thus, the effective benefit of the reparative approach may have been underestimated. In this context, recent innovations in cardiac imaging allow very accurate assessment of mitral valve geometry and have reopened the debate on surgical treatment of the subvalvar apparatus and ventricular wall as a potential key point in ischemic MR (21–24). The evidence suggests that an effective mitral repair approach needs to address the entire mitral complex, including not only the mitral annulus, but also the subvalvular apparatus. We pioneered the use of papillary muscle approximation (PMA) for ischemic MR in combination with restrictive undersizing annuloplasty (RA) with encouraging results, and other evidence on the use of this technique and on papillary muscle relocation produced survival benefit (12–14,21–24). However, the consensus about the role of papillary muscle surgery in ischemic MR is not unanimous, and there is not a univocal surgical attitude towards subvalvular repair in ischemic MR treatment (25,26), as demonstrated in a recent systematic analysis (11). Therefore, a randomized study was designed to compare standard RA alone with the combined annular and subvalvular approach, and to investigate the relative role of papillary muscle surgery in the context of ischemic MR. We also sought to elucidate the effective benefit of papillary muscle surgery in long-term follow-up of ischemic MR, with the aim of determining the optimal surgical strategy in these cases.

Methods

Study design

This study was a prospective, randomized clinical trial that aimed to evaluate patients with severe chronic ischemic MR who underwent either isolated RA or PMA, associated with complete surgical myocardial revascularization. The trial was designed to enroll 96 patients and to evaluate them over a 5-year follow-up. The study was conducted in 1 referring center (Università Campus Bio-Medico di Roma, Rome, Italy) and recruited patients from 3 different regions in central Italy (Lazio, Campania, Abruzzo). Enrollment began in May 2007 and was completed in November 2010. Three different surgeons performed the surgical procedures. The aim of the study was to describe each patient in the cohort over a 5-year follow-up; the study concluded in November 2015. Endpoints were measured at 30 days, at 6 months, and every year thereafter with an outpatient visit and transthoracic echocardiography.

An independent coordinator was in charge of assessing causes of death and adverse events, and results were stored and stratified for the further complete analysis. Simple randomization was performed after study eligibility was checked, and the patient received a detailed explanation of the study’s aim. All patients provided written informed consent for enrollment in the study and for the surgical procedure. The study was not supported by any external source of funding, and no valve manufacturer had any role in the study. The local ethical committee approved the study protocol, which conforms to the Declaration of Helsinki. A study flowchart and a checklist according to the CONSORT (Consolidated Standards of Reporting Trials) protocol are provided, although the study commenced before 2010 (Figure 1, Online Appendix).

Patients

Adults with severe ischemic MR and multivessel coronary artery disease who were symptomatic for congestive heart failure and unresponsive to medical therapy were eligible for surgical repair and coronary artery bypass graft (CABG). The severity of ischemic MR was evaluated by transthoracic echocardiography, which was performed using European Society of Echocardiography criteria (27). Two independent, experienced cardiologists, blinded with regard to the treatment group, assessed all echocardiographic measurements. Severe MR was defined as an effective regurgitant orifice area (EROA) of at least 0.4 cm2 or by a combination of adjunctive echocardiographic quantification methods according to guidelines (27). MR grade was defined according to EROA, which is considered the most reliable method to estimate MR (1) because it is more objective and less load-dependent than regurgitant volume (15). However, final assessment of MR severity was performed using an additive methodology, including analysis of all aspects of the color Doppler jet, such as the jet area/left atrial area ratio and vena contracta. In addition, supportive data, such as left atrial size, E-wave peak, and presence of pulmonary vein flow reversal were incorporated into the assessment, according to guidelines (27).

The aim of this study was to establish the benefit of papillary muscle surgery as an adjunct in the context of the standard mitral repair treatment for ischemic MR. For this reason, geometric and functional LV parameters were selected as primary endpoints with the aim of assessing the efficacy of the technique. In addition, considering their known association with clinical outcomes, NYHA functional class, rates of hospitalization, and survival (28–32), ventricular diameters provided a realistic and effective understanding of both the remodeling process and clinical benefit.

The Minnesota Living with Heart Failure questionnaire, the physical and mental subscales of the Medical Outcomes Study 12-Item Short Form Health Survey, and the EuroQol Group 5-Dimension Self-Report Questionnaire were used to assess QOL among survivors at the end of the study.

Interventions, echocardiography measurements, and statistical analysis are provided in the Online Appendix.

Results

Patients

From May 2007 to November 2010, 124 patients with severe ischemic MR were evaluated; 96 patients were eligible for the study and underwent randomization for mitral valve surgery with CABG (48 to PMA and 48 to RA). Figure 1 presents the study flowchart.

Table 1 shows baseline characteristics and surgical data, and Table 2 shows the clinical outcomes. The echocardiographic evaluation confirmed the presence of severe MR in all patients, and heart failure therapies were similar. Concomitant CABG was performed in all patients, and annuloplasty ring size was similar between groups. Aortic cross-clamp time and cardiopulmonary bypass time were longer in patients who underwent PMA due to the increased procedural time to perform papillary muscle approximation. Post-operative mitral valve configuration, which was evaluated using transesophageal echocardiography, was significantly different between the groups (Table 3).

Left ventricular dimension and function

Table 4 shows echocardiographic parameters at baseline and at 1, 2, and 5 years after surgery. Pre-operative LVEDD was 61.4 ± 3.7 mm in the RA group and 62.7 ± 3.4 mm in the PMA group. The assessment of LVEDD at 5 years showed a significant between-group difference compared with the pre-operative value; LVEDD was 56.5 ± 5.7 mm in the PMA group versus 60.6 ± 4.6 mm with RA alone (observed changes, expressed as paired 5-year values minus pre-operative values, were −5.8 ± 4.1 mm and −0.2 ± 2.3 mm, respectively; p < 0.001; effect size was 1.67 with 95% confidence interval: 1.12 to 2.20). Therefore, there was a significant improvement of LVEDD in both groups 1 year after surgery, with no statistically significant difference between the PMA and RA populations. However, over time, progressive LV enlargement was observed in the RA group, with values almost similar to pre-operative measurements, whereas the PMA group maintained the benefit achieved soon after surgery, with significantly reduced diameters with respect to baseline at the 5-year follow-up. Differences in ejection fraction showed greater recovery of LV function in the PMA group (Table 5).

Comparison of Echocardiographic Parameters, QOL, and Functional Status After 5 Years of Follow-Up

Death and the composite cardiac endpoint

Table 2 lists the clinical outcomes of all patients during follow-up. In-hospital death occurred in 7 patients (4 in the RA and 3 in the PMA group) without statistically significant differences between the 2 groups (p = 1.000). At the end of the study, the cumulative mortality rate was not significantly different between the PMA and RA groups, with 11 (22.9%) and 14 (29.2%) events, respectively (Figure 2A).

(A) Rates of death and the (B and C) composite cardiac endpoint. The composite endpoint of the rate of major adverse cardiac or cerebrovascular events included cardiac death, stroke, subsequent mitral valve surgery, rehospitalization, and an increase in the New York Heart Association functional class of 1 or more. Vertical marks indicate that patients’ data were censored at that point. PMA = papillary muscle approximation with undersizing restrictive mitral annuloplasty; RA = restrictive mitral annuloplasty.

With respect to the recurrence of moderate-to-severe MR, there was no significant difference between the 2 study groups in the immediate post-operative period (Table 3). At the 1-year follow-up, the 2 groups were still comparable, with 2.6% of patients experiencing moderate-to-severe MR recurrence in the RA arm and 7.5% in the PMA arm (p = 0.330). Similarly, no statistically significant difference between the 2 groups was demonstrated after 2 years (RA 13.2% vs. PMA 15.0%) (Table 4). However, after analyzing the progression of MR recurrence over the entire length of the study, we found a statistically significant difference between the 2 groups at the 5-year follow-up, with 55.9% (n = 19) in the RA group and 27.0% (n = 10) in the PMA group having moderate or severe MR (p = 0.013). The proportion of surviving patients with recurrence of severe MR at 5 years was higher in the RA group (n = 8) than in the PMA group (n = 4), but this result failed to reach statistical significance (23.5% vs. 10.8%, respectively; p = 0.153).

Similarly, the total reoperation rate for mitral repair failure over the entire follow-up was 14.6% in the RA group (n = 7) and 6.2% in the PMA group (n = 3), but this difference did not reach statistical significance (p = 0.181). The PMA group showed a significantly reduced tenting area at the 5-year follow-up (p < 0.001) (Table 3). End-systolic and end-diastolic interpapillary distances soon after surgery were significantly reduced compared with pre-operative values in the PMA group only. At the end of follow-up, the interpapillary distance in the RA group progressively increased, reaching values similar to pre-operative end-systolic and end-diastolic measurements (Tables 3 and 4). Table 4 shows between-group and within-group differences in echocardiographic measurements during follow-up.

Rehospitalization for heart failure and worsening of NYHA functional class tended to be lower in the PMA group, yet those results are not statistically significant. Rehospitalization occurred in 35.4% in the RA group and 20.8% in the PMA group (p = 0.112), whereas post-operative worsening of NYHA functional class was experienced by 41.7% who underwent RA and 25.0% who underwent PMA (p = 0.083).

At 5 years, there were no significant between-group differences with respect to the composite endpoint of MACCE, with 45 events in the RA group and 34 events in the PMA group (Figure 2B). However, the incidence of MACCE was significantly reduced in the PMA group in the last year of follow-up (Figure 2C).

Quality of life

No significant differences between the 2 study groups in any measure of QOL or functional status at 5 years were observed (Table 5). Heart failure symptoms according to the Minnesota Living with Heart Failure questionnaire were reduced from baseline in 41.6% in the PMA group and by 43.6% in the RA group. The Medical Outcomes Study 12-Item Short Form Health Survey physical subscale score showed an improvement over baseline in physical health of 15.4% in the PMA group and 14.7% in the RA group.

Discussion

The results of this randomized study revealed the following: 1) improved LV function and decreased LV dimension in PMA was achieved over time in comparison with RA alone, with stable ventricular diameters over 5 years of follow-up; 2) more effective recovery of the geometry of mitral valve configuration in patients who underwent PMA compared with isolated RA in mid- and long-term follow-up; 3) no significant differences between groups in overall mortality and QOL at 30 days, 12 months, and 5 years; 4) a statistically significant difference in the incidence of MACCE, which favored the PMA group over the long term; and 5) a statistically significant lower incidence of moderate-to-severe MR after surgery in the PMA group.

This randomized study demonstrated superiority in terms of ventricular geometry, remodeling, and the function of a combined approach entailing papillary muscle surgery (Central Illustration) and annuloplasty over standard annuloplasty alone in ischemic MR. However, this benefit did not produce a significant survival advantage. The data demonstrated a significant and stable improvement of LVEDD, LV end-systolic diameter, and ejection fraction in the PMA group; progressive enlargement of ventricular cavities and decline in LV function were observed in the RA alone group, indicating that RA was not able to counteract or prevent the negative remodeling that occurred over time in ischemic MR. These findings also confirm the importance of ventricular pathology as a pivotal factor in ischemic MR. The high absolute values of the LVEDD and LV end-systolic diameter, and the rate of MR recurrence observed in this study in comparison with other published studies (13,14,32) might suggest that neither PMA nor RA alone can completely solve the physiopathological course of ischemic MR, because they do not address the role of the ventricle. In support of this idea, Wakasa et al. suggested the effectiveness of a combined approach that involved annuloplasty, papillary muscle surgery, and ventricular procedures to ameliorate clinical outcomes of ischemic MR (33). Conversely, improvement in LV dimension and remodeling in the present study was better than that in the recent report by Goldstein et al. (15). These differences might primarily be due to the fact that our entire study population underwent complete myocardial revascularization, whereas only 73% of patients in the aforementioned trial underwent revascularization. Twenty percent of those patients had already undergone previous CABG, and 35% had a previous percutaneous transluminal coronary angioplasty procedure, whereas our study had no redo cases. The lack of myocardial revascularization and the previous coronary intervention might justify the worse long-term results in terms of LV remodeling. Furthermore, our study population was 5 years younger, which reliably accounted for better long-term outcomes. Moreover, according to Goldstein et al. (15), the baseline ejection fraction in their study was 40 ± 11%, which indicated a more heterogeneous patient population than in our study, and 30% of their patients had an internal cardioverter-defibrillator implanted.

MR recurrence after surgery has a reported occurrence that ranges widely across studies, from 5% to 58% (12–15,25,32). This variability might be related to the different population profiles, adjustment for baseline characteristics, differences in the actual procedure performed, and follow-up times in nonrandomized studies. We confirmed that among survivors, the rate of moderate-to-severe recurrent MR at 5 years was 55.9% in the RA group versus 27.0% in the PMA group. Both the incidence (15) and the time course of MR recurrence mirrored those reported in previous studies, in which the 1-year prevalence of moderate-to-severe MR after RA alone ranged between 2% and 4%, but increased substantially over time in the long term (11). However, a degree of discrepancy can be appreciated when comparing the data with that of Goldstein et al. (15), who reported a 58.8% incidence of moderate-to-severe MR at 2 years, whereas it ranged between 13% and 15% in our cohort. As discussed previously, the lack of revascularization and the different baseline clinical characteristics might allow us to foresee the onset of more rapid LV negative remodeling in their population, with consequent geometric changes of the LV and subvalvular apparatus and recurrence of MR. The presence of residual myocardial ischemia will determine the persistence of an imbalance between closing and tethering forces, favoring MR recurrence. Moreover, the extent of annulus restriction produced by the RA procedure is crucial in determining the valve’s long-term competence. In their study, Goldstein et al. (15) reported an average valve annulus size of 31.0 mm, and an average ring size of 27.9 mm, but 93% of patients received a ring measuring ≤30 mm. Despite the known importance of fold-size reduction with respect to the baseline annulus dimension, the absolute values differed significantly in our study, in which the native annulus was 39.5 ± 1.8 mm and the average ring size implanted was 27.1 ± 1.2 mm, indicating a higher degree of retraction applied and more significant undersizing in absolute numbers. This might explain the short-term reduced tendency of MR recurrence observed in our study. In addition, our study was performed in a single center by 3 surgeons, whereas the trial by Goldstein et al. (15) was a multicenter study involving 26 centers with a presumably high number of surgeons involved. Despite both studies having mortality limited to within the American and European standards, indicating no bias related to the effect of different expertise among surgeons, differences in personal experience and habits, and center policies might have played a role.

The improved LV and mitral geometric configuration did not translate to a long-term survival advantage for the PMA group over the RA group. The baseline depressed cardiac function (<40% in both groups, without significant differences at baseline) and the enlarged ventricular dimensions (>60 mm in both groups, without significant differences at baseline) might justify the mortality rate in this study and explain the differences with other studies reporting better survival rates, in which baseline clinical conditions were significantly better and follow-ups were shorter (12–14). However, 30-day mortality was comparable in the United States and Europe (34,35), indicating that surgical biases or inexperience did not affect the reliability of the results.

Analysis of the composite cardiac endpoint, including MACCE, did not reveal statistically significant differences between the 2 groups in the first 3 years after surgery. However, between the fourth and fifth year of follow-up, we could detect a significant decrease in the rate of adverse cardiac events in the PMA group. This finding suggests a long-term protective effect of papillary muscle surgery that, in combination with a stably reduced LVEDD and improved LV function, decreases the cumulative incidence of adverse events. We can reliably speculate that approximation of anterior and posterior papillary muscles induced a geometric “restraint effect” on the LV, which in combination with the stable resolution of the MR, produced a durable hemodynamic advantage in these patients. Supporting this hypothesis, PMA produced a statistically significant decreased recurrence of moderate-to-severe MR after surgery. However, several intertwined factors are involved and outside of these hypothetical interpretations, none of these improved geometric and functional parameters produced significant improvement in survival and in patients’ QOL or functional status. While awaiting larger trials with prolonged follow-up to confirm and extend the results of this study, which demonstrated a survival benefit and an advantage in QOL using papillary muscle surgery, enthusiasm for this approach should be tempered and a word of caution spent in this context.

However, in accordance with the primary endpoint of this trial, the final results demonstrated superiority of the combination of papillary muscle surgery and RA in improving LV geometry and function, and in restoring adequate mitral configuration and function over RA alone. This augmented surgical efficacy translated to a long-term benefit in the occurrence of cardiac adverse events and MR recurrence, but did not produce a significant advantage in long-term survival and improvement in functional clinical status.

Study limitations

The primary endpoint relied on an echocardiographic measure of LV remodeling, rather than a clinical outcome (e.g., mortality), which was a study limitation. However, such a randomized trial would have required a large number of patients to achieve statistical power, which would have largely exceeded timely enrollment in this study. As described in the discussion, this study aimed to define a difference in the surgical efficacy of the combined PMA approach to consider a possible step change in current surgical practice. Therefore, a routinely and universally used and recognized set of echocardiographic parameters seemed the most suitable approach in this setting. However, we are aware that there may be operator-dependent fluctuations in data interpretation with transthoracic echocardiography. In this study, 2 blinded experienced cardiologists performed all echocardiograms with an adequate inter-rater variability coefficient and provided results with sufficient reliability. Also, underestimation or overestimation of EF might occur in MR, but these parameters were adjusted in consideration of the transmitral gradient and the inflow velocity. However, to circumvent these issues, the use of computed tomography or cardiac magnetic resonance should be advocated.

Conclusions

PMA exerted a long-term beneficial effect on LV remodeling and provided more effective restoration of mitral valve geometric configuration in ischemic MR than RA alone. Together, these findings resulted in improved long-term cardiac outcomes, but did not produce differences in overall mortality and QOL. From the experience acquired, we might conclude that the “Achilles heel” of mitral repair in ischemic MR is the long-term adverse LV remodeling that influences geometric relationships within the ventricle, which dramatically affects the equilibrium between the closing and tethering forces at the level of both the annulus and the subvalvular apparatus. The presumed inferiority of mitral repair compared with valve replacement might be related to these geometric abnormalities. Papillary muscle surgery together with complete myocardial revascularization can address these issues, improving the generally negative outcomes of this procedure. However, additional investigations on this subject, together with direct comparison to a “complete” repair strategy, including both PMA and RA, versus chordal-sparing mitral replacement should be advocated.

However, we believe that the data presented herein could guide the decision-making process for the surgical strategy and assist patient counseling about expectations for surgery in ischemic MR.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with severe ischemic MR who are undergoing mitral valve repair and revascularization surgery, combining papillary muscle approximation with RA results in better LV geometry and function and less recurrent MR than restrictive mitral annuloplasty without approximation of the subvalvular apparatus, but there was no difference in 5-year survival.

(2011) 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol58:e123–e210.

(2009) Continued global left ventricular remodeling is not the sole mechanism responsible for the late recurrence of ischemic mitral regurgitation after restrictive annuloplasty. J Am Soc Echocardiogr22:1256–1264.

(2009) Recommendations for evaluation of prosthetic valves with echocardiography and Doppler ultrasound: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Task Force on Prosthetic Valves, developed in conjunction with the American College of Cardiology Cardiovascular Imaging Committee, Cardiac Imaging Committee of the American Heart Association, the European Association of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society of Echocardiography and the Canadian Society of Echocardiography, Endorsed by the American College of Cardiology Foundation, American Heart Association, European Association of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society of Echocardiography, and Canadian Society of Echocardiography. J Am Soc Echocardiogr22:975–1014, quiz 1082–4.

(1997) Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation96:3294–3299.

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